ABSTRACT
Timely fluid administration is crucial to maintain tissue perfusion in septic shock patients. However, the question concerning which fluid should be used for septic shock resuscitation remains a matter of debate. A growing body of evidence suggests that the type, amount and timing of fluid administration during the course of sepsis may affect patient outcomes. Crystalloids have been recommended as the first-line fluids for septic shock resuscitation. Nevertheless, given the inconclusive nature of the available literature, no definitive recommendations about the most appropriate crystalloid solution can be made. Resuscitation of septic and non-septic critically ill patients with unbalanced crystalloids, mainly 0.9% saline, has been associated with a higher incidence of acid-base balance and electrolyte disorders and might be associated with a higher incidence of acute kidney injury. This can result in greater demand for renal replacement therapy and increased mortality. Balanced crystalloids have been proposed as an alternative to unbalanced solutions in order to mitigate their detrimental effects. Nevertheless, the safety and effectiveness of balanced crystalloids for septic shock resuscitation need to be further addressed in a well-designed, multicenter, pragmatic, randomized controlled trial.
Keywords:
Fluid therapy/methods; Isotonic solutions/administration & dosage; Rehydration solutions/administration & dosage; Shock, septic; Resuscitation/methods; Critical care/methods; Critical care/trends
RESUMO
A administração de fluidos em tempo adequado é crucial para a manutenção da perfusão tissular nos pacientes com choque séptico. Entretanto, a questão da escolha do fluido a ser utilizado para ressuscitação no choque séptico ainda é um assunto em debate. É crescente o corpo de evidência que sugere que o tipo, a quantidade e o momento da administração de fluidos durante a evolução da sepse podem afetar os desfechos do paciente. Os cristaloides têm sido recomendados como fluidos a serem administrados em primeira linha na ressuscitação do choque. No entanto, à luz da natureza inconclusiva da literatura disponível, não se podem fazer recomendações definitivas quanto à solução cristaloide mais apropriada. A ressuscitação de pacientes críticos sépticos e não sépticos com cristaloides não balanceados, principalmente a solução salina a 0,9%, tem sido associada a uma maior incidência de desordens do equilíbrio ácido-base e a distúrbios eletrolíticos, além de poder se associar à maior incidência de lesão renal aguda, à maior necessidade de terapia de substituição renal e à mortalidade. Foi proposto o uso de soluções cristaloides balanceadas como uma alternativa às soluções de cristaloides não balanceados, para mitigar seus efeitos deletérios. Entretanto, a segurança e a eficácia dos cristaloides balanceados para ressuscitação do choque séptico necessitam ser mais bem exploradas em estudos clínicos bem delineados, randomizados e controlados, multicêntricos e pragmáticos.
Descritores:
Hidratação/métodos; Soluções isotônicas/administração & dosagem; Soluções para reidratação/administração & dosagem; Choque séptico; Ressuscitação/métodos; Cuidados críticos/métodos; Cuidados críticos/tendências
INTRODUCTION
Septic shock is characterized by intense systemic vasodilation with varying degrees of hypovolemia.(11 Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840-51. Review. Erratum in: N Engl J Med. 2013;369(21):2069.) Timely fluid administration is crucial to improve cardiac output, restore oxygen delivery and reverse tissue hypoxia.(11 Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840-51. Review. Erratum in: N Engl J Med. 2013;369(21):2069.) As a result, cellular and mitochondrial dysfunction as well as progression to multiple organ dysfunction syndrome secondary to systemic inflammation and tissue hypoperfusion are mitigated.(11 Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840-51. Review. Erratum in: N Engl J Med. 2013;369(21):2069.) Therefore, fluid administration is recommended as a first-line intervention to resuscitate septic shock patients.(22 Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165-228.)
A growing body of evidence suggests that the type, amount and timing of fluid administration during the course of sepsis may affect patient outcomes.(33 Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369(13):1243-51. Review.) While early fluid administration has been associated with decreased in-hospital mortality,(44 Lee SJ, Ramar K, Park JG, Gajic O, Li G, Kashyap R. Increased fluid administration in the first three hours of sepsis resuscitation is associated with reduced mortality: a retrospective cohort study. Chest. 2014;146(4):908-15.) delayed resuscitation has been associated with a pronounced release of inflammatory mediators and decreased skeletal muscle adenosine triphosphate content and mitochondrial dysfunction.(55 Corrêa TD, Vuda M, Blaser AR, Takala J, Djafarzadeh S, Dünser MW, et al. Effect of treatment delay on disease severity and need for resuscitation in porcine fecal peritonitis. Crit Care Med. 2012;40(10):2841-9.) Furthermore, liberal fluid administration to septic shock patients yields a net positive fluid balance, which may contribute to organ failure and poor outcomes.(66 Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med. 2011;39(2):259-65.)
Many types of fluids are available for clinicians at the bedside.(33 Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369(13):1243-51. Review.) Nevertheless, since the type and amount of administered fluids affect patient-centered outcomes,(77 Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, Mbuagbaw L, Szczeklik W, Alshamsi F, Altayyar S, Ip WC, Li G, Wang M, Wludarczyk A, Zhou Q, Guyatt GH, Cook DJ, Jaeschke R, Annane D; Fluids in Sepsis and Septic Shock Group. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014;161(5):347-55. Review.,88 Rochwerg B, Alhazzani W, Gibson A, Ribic CM, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, Mbuagbaw L, Szczeklik W, Alshamsi F, Altayyar S, Ip W, Li G, Wang M, Wludarczyk A, Zhou Q, Annane D, Cook DJ, Jaeschke R, Guyatt GH; FISSH Group (Fluids in Sepsis and Septic Shock) . Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis. Intensive Care Med. 2015;41(9):1561-71. Review.) such drugs should be prescribed with caution.(33 Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369(13):1243-51. Review.) Moreover, it is important to emphasize that fluid administration should be indicated only for those who have impaired tissue perfusion and are deemed fluid responsive (i.e., patients with a high likelihood of improving cardiac output after fluid administration).(99 Cecconi M, Hofer C, Teboul JL, Pettila V, Wilkman E, Molnar Z, Della Rocca G, Aldecoa C, Artigas A, Jog S, Sander M, Spies C, Lefrant JY, De Backer D; FENICE Investigators.; ESICM Trial Group. Fluid challenges in intensive care: the FENICE study: A global inception cohort study. Intensive Care Med. 2015;41(9):1529-37. Erratum in: Intensive Care Med. 2015;41(9):1737-8. multiple investigator names added.) Whenever fluids are judged necessary, clear endpoints of efficacy and safety must be defined in advance in order to maximize the efficacy of the fluids administered and minimize their potential detrimental effects.(99 Cecconi M, Hofer C, Teboul JL, Pettila V, Wilkman E, Molnar Z, Della Rocca G, Aldecoa C, Artigas A, Jog S, Sander M, Spies C, Lefrant JY, De Backer D; FENICE Investigators.; ESICM Trial Group. Fluid challenges in intensive care: the FENICE study: A global inception cohort study. Intensive Care Med. 2015;41(9):1529-37. Erratum in: Intensive Care Med. 2015;41(9):1737-8. multiple investigator names added.)
The question concerning which fluid should be used during septic shock resuscitation remains a matter of debate.(1010 Orbegozo Cortés D, Rayo Bonor A, Vincent JL. Isotonic crystalloid solutions: a structured review of the literature. Br J Anaesth. 2014;112(6):968-81.) The current Surviving Sepsis Campaign Guidelines recommend crystalloids as first-line fluids for septic shock resuscitation.(22 Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165-228.) Nevertheless, no consensus has been reached regarding which crystalloid, i.e., unbalanced or balanced, is the most appropriate in this context.(1111 Raghunathan K, Murray PT, Beattie WS, Lobo DN, Myburgh J, Sladen R, Kellum JA, Mythen MG, Shaw AD; ADQI XII Investigators Group. Choice of fluid in acute illness: what should be given? An international consensus. Br J Anaesth. 2014;113(5):772-83.)
This narrative review briefly discusses the main physicochemical properties of unbalanced and balanced crystalloids as well as their main advantages and drawbacks. It also presents evidence supporting balanced crystalloids as the fluids of choice for septic shock resuscitation.
This narrative literature review includes articles published in the MEDLINE/PubMed database until March 2016 that addressed crystalloid fluid resuscitation in critically ill patients. We used the search term "balanced solution" and search filters for systematic reviews (systematic [sb]) and randomized trials (((clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials as topic[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/Abstract] OR random allocation[MeSH Terms] OR therapeutic use[MeSH Subheading])).(1212 Haynes RB, McKibbon KA, Wilczynski NL, Walter SD, Werre SR; Hedges Team. Optimal search strategies for retrieving scientifically strong studies of treatment from Medline: analytical survey. BMJ. 2005;330(7501):1179.) The search retrieved 433 references. After title and abstract screening, we selected the full-text versions of 95 relevant citations for a thorough analysis. We also searched reference lists of the retrieved manuscripts to identify other relevant studies.
CRYSTALLOIDS
Solutions containing water and freely permeable ions, mainly sodium and chloride, are classified as crystalloids (Table 1).(33 Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369(13):1243-51. Review.) Some of these solutions have other ions, such as potassium, calcium or magnesium, and may have buffers, most commonly bicarbonate, lactate, acetate or gluconate, to maintain electroneutrality (balance between positive and negative ions).(33 Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369(13):1243-51. Review.) Crystalloid solutions may be hypotonic, isotonic or hypertonic in relation to human plasma.(33 Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369(13):1243-51. Review.) A crystalloid solution is considered balanced when it has a strong ion difference (SID) close to 24mEq/L,(1313 Morgan TJ. The ideal crystalloid - what is 'balanced'? Curr Opin Crit Care. 2013;19(4):299-307.) which can be achieved by replacing varying amounts of chloride from 0.9% saline with bicarbonate, lactate or acetate (Table 1).(33 Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369(13):1243-51. Review.)
Unbalanced crystalloids
Sodium chloride (0.9% saline) is the most available and frequently used crystalloid worldwide.(33 Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369(13):1243-51. Review.) Sodium chloride is an isotonic solution (osmolality closer to that of human plasma) that contains equal concentrations of sodium and chloride (154mmol/L, each) and therefore has an SID equal to zero (Table 1). Experimental(1414 Zhou F, Peng ZY, Bishop JV, Cove ME, Singbartl K, Kellum JA. Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis*. Crit Care Med. 2014;42(4):e270-8.
15 Healey MA, Davis RE, Liu FC, Loomis WH, Hoyt DB. Lactated ringer's is superior to normal saline in a model of massive hemorrhage and resuscitation. J Trauma. 1998;45(5):894-9.
16 Watters JM, Brundage SI, Todd SR, Zautke NA, Stefater JA, Lam JC, et al. Resuscitation with lactated ringer's does not increase inflammatory response in a Swine model of uncontrolled hemorrhagic shock. Shock. 2004;22(3):283-7.
17 Todd SR, Malinoski D, Muller PJ, Schreiber MA. Lactated Ringer's is superior to normal saline in the resuscitation of uncontrolled hemorrhagic shock. J Trauma. 2007;62(3):636-9.
18 Noritomi DT, Pereira AJ, Bugano DD, Rehder PS, Silva E. Impact of Plasma-Lyte pH 7.4 on acid-base status and hemodynamics in a model of controlled hemorrhagic shock. Clinics (São Paulo). 2011;66(11):1969-74.
19 Rohrig R, Rönn T, Lendemans S, Feldkamp T, de Groot H, Petrat F. Adverse effects of resuscitation with lactated ringer compared with ringer solution after severe hemorrhagic shock in rats. Shock. 2012;38(2):137-45.
20 Aksu U, Bezemer R, Yavuz B, Kandil A, Demirci C, Ince C. Balanced vs unbalanced crystalloid resuscitation in a near-fatal model of hemorrhagic shock and the effects on renal oxygenation, oxidative stress, and inflammation. Resuscitation. 2012;83(6):767-73.
21 Martini WZ, Cortez DS, Dubick MA. Comparisons of normal saline and lactated Ringer's resuscitation on hemodynamics, metabolic responses, and coagulation in pigs after severe hemorrhagic shock. Scand J Trauma Resusc Emerg Med. 2013;21:86.-2222 Rohrig R, Wegewitz C, Lendemans S, Petrat F, de Groot H. Superiority of acetate compared with lactate in a rodent model of severe hemorrhagic shock. J Surg Res. 2014;186(1):338-45.) (Table 2) and clinical(2323 McFarlane C, Lee A. A comparison of Plasmalyte 148 and 0.9% saline for intra-operative fluid replacement. Anaesthesia. 1994;49(9):779-81.
24 Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal saline versus lactated Ringer's solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg. 2001;93(4):817-22.
25 Takil A, Eti Z, Irmak P, Yilmaz Gögüs F. Early postoperative respiratory acidosis after large intravascular volume infusion of lactated ringer's solution during major spine surgery. Anesth Analg. 2002;95(2):294-8, table of contents.
26 Young JB, Utter GH, Schermer CR, Galante JM, Phan HH, Yang Y, et al. Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial. Ann Surg. 2014;259(2):255-62.
27 Smith CA, Gosselin RC, Utter GH, Galante JM, Young JB, Scherer LA, et al. Does saline resuscitation affect mechanisms of coagulopathy in critically ill trauma patients? An exploratory analysis. Blood Coagul Fibrinolysis. 2015;26(3):250-4.
28 O'Malley CM, Frumento RJ, Hardy MA, Benvenisty AI, Brentjens TE, Mercer JS, et al. A randomized, double-blind comparison of lactated Ringer's solution and 0.9% NaCl during renal transplantation. Anesth Analg. 2005;100(5):1518-24, table of contents.
29 Khajavi MR, Etezadi F, Moharari RS, Imani F, Meysamie AP, Khashayar P, et al. Effects of normal saline vs. lactated ringer's during renal transplantation. Ren Fail. 2008;30(5):535-9.
30 Hadimioglu N, Saadawy I, Saglam T, Ertug Z, Dinckan A. The effect of different crystalloid solutions on acid-base balance and early kidney function after kidney transplantation. Anesth Analg. 2008;107(1):264-9.
31 Modi MP, Vora KS, Parikh GP, Shah VR. A comparative study of impact of infusion of Ringer's Lactate solution versus normal saline on acid-base balance and serum electrolytes during live related renal transplantation. Saudi J Kidney Dis Transpl. 2012;23(1):135-7.
32 Kim SY, Huh KH, Lee JR, Kim SH, Jeong SH, Choi YS. Comparison of the effects of normal saline versus Plasmalyte on acid-base balance during living donor kidney transplantation using the Stewart and base excess methods. Transplant Proc. 2013;45(6):2191-6.
33 Mahler SA, Conrad SA, Wang H, Arnold TC. Resuscitation with balanced electrolyte solution prevents hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis. Am J Emerg Med. 2011;29(6):670-4.
34 Van Zyl DG, Rheeder P, Delport E. Fluid management in diabetic-acidosis-Ringer's lactate versus normal saline: a randomized controlled trial. QJM. 2012;105(4):337-43.
35 Hasman H, Cinar O, Uzun A, Cevik E, Jay L, Comert B. A randomized clinical trial comparing the effect of rapidly infused crystalloids on acid-base status in dehydrated patients in the emergency department. Int J Med Sci. 2012;9(1):59-64.
36 Cieza JA, Hinostroza J, Huapaya JA, León CP. Sodium chloride 0.9% versus Lactated Ringer in the management of severely dehydrated patients with choleriform diarrhoea. J Infect Dev Ctries. 2013;7(7):528-32.-3737 Wu BU, Hwang JQ, Gardner TH, Repas K, Delee R, Yu S, et al. Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol. 2011;9(8):710-717.e1.) studies (Table 3) have suggested that resuscitation with 0.9% saline has detrimental effects on the kidneys, acid-base balance, and electrolyte homeostasis and may affect tissue perfusion,(3838 Gruartmoner G, Mesquida J, Ince C. Fluid therapy and the hypovolemic microcirculation. Curr Opin Crit Care. 2015;21(4):276-84.) inflammatory response,(1414 Zhou F, Peng ZY, Bishop JV, Cove ME, Singbartl K, Kellum JA. Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis*. Crit Care Med. 2014;42(4):e270-8.) and coagulation (dilutional coagulopathy and/or profound hyperchloremic metabolic acidosis).(2727 Smith CA, Gosselin RC, Utter GH, Galante JM, Young JB, Scherer LA, et al. Does saline resuscitation affect mechanisms of coagulopathy in critically ill trauma patients? An exploratory analysis. Blood Coagul Fibrinolysis. 2015;26(3):250-4.,3939 Kozek-Langenecker SA. Fluids and coagulation. Curr Opin Crit Care. 2015;21(4):285-91.)
Summary of randomized controlled trials comparing balanced with unbalanced crystalloids in clinical-surgical critically ill patients
Hyperchloremia adversely affects kidney function.(4040 Martensson J, Bellomo R. Are all fluids bad for the kidney? Curr Opin Crit Care. 2015;21(4):292-301.) Intrarenal (kidney artery) infusion of chloride-containing solutions, such as 0.9% saline or ammonium chloride (NH4Cl), leads to a reduced renal artery blood flow and glomerular filtration rate in kidneys isolated from healthy dogs.(4141 Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest. 1983;71(3):726-35.) Intravascular volume expansion with solutions containing supraphysiological chloride concentrations, such as 0.9% saline, leads to increased chloride delivery to the macula densa cells localized to the distal nephrons.(4040 Martensson J, Bellomo R. Are all fluids bad for the kidney? Curr Opin Crit Care. 2015;21(4):292-301.) As a result, a number of signaling mediators, such as adenosine, are released from macula densa cells into the kidney circulation (tubuloglomerular feedback).(4242 Vallon V, Mühlbauer B, Osswald H. Adenosine and kidney function. Physiol Rev. 2006;86(3):901-40.) Adenosine has a strong constrictive effect on the renal afferent arteriole, which compromises the renal blood flow, glomerular filtration rate and, ultimately, kidney function.(4040 Martensson J, Bellomo R. Are all fluids bad for the kidney? Curr Opin Crit Care. 2015;21(4):292-301.)
The impact of intravascular volume expansion with unbalanced solutions (0.9% saline) containing supraphysiological amounts of chloride on acid-base balance and electrolyte homeostasis are better explained by the physicochemical Stewart approach.(4343 Seifter JL. Integration of acid-base and electrolyte disorders. N Engl J Med. 2014;371(19):1821-31.) Accordingly, strong cations (Na+, K+, Mg2+ and Ca2+) predominate in relation to strong anions (Cl-) in the body, producing a net positive plasma charge of approximately 40mmol/L, which is also known as the SID.(4343 Seifter JL. Integration of acid-base and electrolyte disorders. N Engl J Med. 2014;371(19):1821-31.) This positive plasma charge must be counterbalanced with an equal negative charge to sustain the electrical neutrality (Law of electro-neutrality). The balancing anionic charge is derived from nonvolatile weak acids, mainly albumin and phosphate.(4343 Seifter JL. Integration of acid-base and electrolyte disorders. N Engl J Med. 2014;371(19):1821-31.) Infusion with large amounts of 0.9% saline produces hyperchloremic metabolic acidosis in healthy volunteers and in different populations of critically ill patients (Table 3).
Hyperchloremic metabolic acidosis occurs because 0.9% saline contains strong cations and strong anions in the same quantity (SID equal to zero). When the plasma chloride concentration increases after 0.9% saline infusion, the net positive charge of plasma (SID) is reduced. Conversely, compensatory mechanisms designed to maintain the plasma electro-neutrality are activated, thus increasing the plasma positive charge (H+) while decreasing the arterial pH.(4343 Seifter JL. Integration of acid-base and electrolyte disorders. N Engl J Med. 2014;371(19):1821-31.)
Balanced crystalloids
Balanced crystalloids have been proposed as an alternative to unbalanced solutions in order to mitigate their detrimental effects.(33 Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369(13):1243-51. Review.) The most commonly available balanced crystalloids are presented in table 1. Ringer's lactate is produced by adding sodium lactate as a buffer to Ringer's solution to reduce its chloride concentration (Table 1). Concerns that large amounts of Ringer's lactate infusion can increase plasma lactate levels in critically ill patients have led to the development of Ringer's acetate, in which the lactate buffer is replaced by acetate.(3030 Hadimioglu N, Saadawy I, Saglam T, Ertug Z, Dinckan A. The effect of different crystalloid solutions on acid-base balance and early kidney function after kidney transplantation. Anesth Analg. 2008;107(1):264-9.) Thus, the composition of Ringer's lactate and Ringer's acetate is almost identical with the exception of the added buffer (lactate or acetate, respectively) (Table 1).
Plasma-Lyte is another balanced solution with an osmolality of 294mOsm/L and sodium and chloride concentrations of 140mmol/L and of 98mmol/L, respectively. Other electrolytes and buffers present in this solution include potassium, magnesium, acetate and gluconate (Table 1). In the next sections, the current evidence comparing balanced and unbalanced crystalloids in experimental models (Table 2) as well as in clinical studies involving healthy volunteers and septic and non-septic critically ill patients (Table 3) is presented.
EXPERIMENTAL STUDIES
Most experimental studies comparing a balanced solution, in general Ringer's lactate or Plasma-Lyte, to an unbalanced solution (0.9% saline) were performed in animal models of hemorrhagic shock(1515 Healey MA, Davis RE, Liu FC, Loomis WH, Hoyt DB. Lactated ringer's is superior to normal saline in a model of massive hemorrhage and resuscitation. J Trauma. 1998;45(5):894-9.
16 Watters JM, Brundage SI, Todd SR, Zautke NA, Stefater JA, Lam JC, et al. Resuscitation with lactated ringer's does not increase inflammatory response in a Swine model of uncontrolled hemorrhagic shock. Shock. 2004;22(3):283-7.
17 Todd SR, Malinoski D, Muller PJ, Schreiber MA. Lactated Ringer's is superior to normal saline in the resuscitation of uncontrolled hemorrhagic shock. J Trauma. 2007;62(3):636-9.
18 Noritomi DT, Pereira AJ, Bugano DD, Rehder PS, Silva E. Impact of Plasma-Lyte pH 7.4 on acid-base status and hemodynamics in a model of controlled hemorrhagic shock. Clinics (São Paulo). 2011;66(11):1969-74.
19 Rohrig R, Rönn T, Lendemans S, Feldkamp T, de Groot H, Petrat F. Adverse effects of resuscitation with lactated ringer compared with ringer solution after severe hemorrhagic shock in rats. Shock. 2012;38(2):137-45.
20 Aksu U, Bezemer R, Yavuz B, Kandil A, Demirci C, Ince C. Balanced vs unbalanced crystalloid resuscitation in a near-fatal model of hemorrhagic shock and the effects on renal oxygenation, oxidative stress, and inflammation. Resuscitation. 2012;83(6):767-73.
21 Martini WZ, Cortez DS, Dubick MA. Comparisons of normal saline and lactated Ringer's resuscitation on hemodynamics, metabolic responses, and coagulation in pigs after severe hemorrhagic shock. Scand J Trauma Resusc Emerg Med. 2013;21:86.-2222 Rohrig R, Wegewitz C, Lendemans S, Petrat F, de Groot H. Superiority of acetate compared with lactate in a rodent model of severe hemorrhagic shock. J Surg Res. 2014;186(1):338-45.) (Table 2). While resuscitation with 0.9% saline, but not with a balanced solution, led to hyperchloremic metabolic acidosis,(1515 Healey MA, Davis RE, Liu FC, Loomis WH, Hoyt DB. Lactated ringer's is superior to normal saline in a model of massive hemorrhage and resuscitation. J Trauma. 1998;45(5):894-9.
16 Watters JM, Brundage SI, Todd SR, Zautke NA, Stefater JA, Lam JC, et al. Resuscitation with lactated ringer's does not increase inflammatory response in a Swine model of uncontrolled hemorrhagic shock. Shock. 2004;22(3):283-7.
17 Todd SR, Malinoski D, Muller PJ, Schreiber MA. Lactated Ringer's is superior to normal saline in the resuscitation of uncontrolled hemorrhagic shock. J Trauma. 2007;62(3):636-9.
18 Noritomi DT, Pereira AJ, Bugano DD, Rehder PS, Silva E. Impact of Plasma-Lyte pH 7.4 on acid-base status and hemodynamics in a model of controlled hemorrhagic shock. Clinics (São Paulo). 2011;66(11):1969-74.
19 Rohrig R, Rönn T, Lendemans S, Feldkamp T, de Groot H, Petrat F. Adverse effects of resuscitation with lactated ringer compared with ringer solution after severe hemorrhagic shock in rats. Shock. 2012;38(2):137-45.
20 Aksu U, Bezemer R, Yavuz B, Kandil A, Demirci C, Ince C. Balanced vs unbalanced crystalloid resuscitation in a near-fatal model of hemorrhagic shock and the effects on renal oxygenation, oxidative stress, and inflammation. Resuscitation. 2012;83(6):767-73.
21 Martini WZ, Cortez DS, Dubick MA. Comparisons of normal saline and lactated Ringer's resuscitation on hemodynamics, metabolic responses, and coagulation in pigs after severe hemorrhagic shock. Scand J Trauma Resusc Emerg Med. 2013;21:86.-2222 Rohrig R, Wegewitz C, Lendemans S, Petrat F, de Groot H. Superiority of acetate compared with lactate in a rodent model of severe hemorrhagic shock. J Surg Res. 2014;186(1):338-45.) renal blood flow and kidney oxygen consumption were improved with Plasma-Lyte resuscitation(2020 Aksu U, Bezemer R, Yavuz B, Kandil A, Demirci C, Ince C. Balanced vs unbalanced crystalloid resuscitation in a near-fatal model of hemorrhagic shock and the effects on renal oxygenation, oxidative stress, and inflammation. Resuscitation. 2012;83(6):767-73.) (Table 2).
Plasma-Lyte was compared to 0.9% saline only in one experimental model of abdominal sepsis (Table 2).(1414 Zhou F, Peng ZY, Bishop JV, Cove ME, Singbartl K, Kellum JA. Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis*. Crit Care Med. 2014;42(4):e270-8.) In this study, rats were randomly allocated to resuscitation with either Plasma-Lyte or 0.9% saline, subcutaneously, eighteen hours after a cecal ligation and puncture.(1414 Zhou F, Peng ZY, Bishop JV, Cove ME, Singbartl K, Kellum JA. Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis*. Crit Care Med. 2014;42(4):e270-8.) Resuscitation with Plasma-Lyte was associated with maintained plasma chloride levels and arterial pH, lower plasma creatinine, lower urinary cystatin C, lower neutrophil gelatinase-associated lipocalin (NGAL), lower plasma interleukin-6 (IL-6), lower incidence (and severity) of acute kidney injury and a higher survival rate than animals resuscitated with 0.9% saline. Serum potassium levels, which are a major concern related to balanced crystalloids containing potassium, did not differ between the groups.(1414 Zhou F, Peng ZY, Bishop JV, Cove ME, Singbartl K, Kellum JA. Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis*. Crit Care Med. 2014;42(4):e270-8.)
STUDIES INVOLVING HEALTHY VOLUNTEERS
Four randomized crossover studies addressed the effects of 0.9% saline, Plasma-Lyte, Ringer's lactate or Hartmann's solution on acid-base balance and electrolyte disorders in healthy volunteers.(4444 Williams EL, Hildebrand KL, McCormick SA, Bedel MJ. The effect of intravenous lactated Ringer's solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers. Anesth Analg. 1999;88(5):999-1003.
45 Reid F, Lobo DN, Williams RN, Rowlands BJ, Allison SP. (Ab)normal saline and physiological Hartmann's solution: a randomized double-blind crossover study. Clin Sci (Lond). 2003;104(1):17-24.
46 Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2012;256(1):18-24.-4747 Story DA, Lees L, Weinberg L, Teoh SY, Lee KJ, Velissaris S, et al. Cognitive changes after saline or plasmalyte infusion in healthy volunteers: a multiple blinded, randomized, cross-over trial. Anesthesiology. 2013;119(3):569-75.) All studies reported hyperchloremic metabolic acidosis following a 0.9% saline infusion.(4444 Williams EL, Hildebrand KL, McCormick SA, Bedel MJ. The effect of intravenous lactated Ringer's solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers. Anesth Analg. 1999;88(5):999-1003.
45 Reid F, Lobo DN, Williams RN, Rowlands BJ, Allison SP. (Ab)normal saline and physiological Hartmann's solution: a randomized double-blind crossover study. Clin Sci (Lond). 2003;104(1):17-24.
46 Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2012;256(1):18-24.-4747 Story DA, Lees L, Weinberg L, Teoh SY, Lee KJ, Velissaris S, et al. Cognitive changes after saline or plasmalyte infusion in healthy volunteers: a multiple blinded, randomized, cross-over trial. Anesthesiology. 2013;119(3):569-75.)
While 50mL/kg of Ringer's lactate infusion transiently decreased serum osmolality and increased venous pH in healthy volunteers, a lower urinary output was seen after the same amount of 0.9% saline infusion.(4444 Williams EL, Hildebrand KL, McCormick SA, Bedel MJ. The effect of intravenous lactated Ringer's solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers. Anesth Analg. 1999;88(5):999-1003.) In another study, Reid et al. infused two liters of 0.9% saline or Hartmann's solution for two hours in healthy volunteers on two separate occasions.(4545 Reid F, Lobo DN, Williams RN, Rowlands BJ, Allison SP. (Ab)normal saline and physiological Hartmann's solution: a randomized double-blind crossover study. Clin Sci (Lond). 2003;104(1):17-24.) In addition to a more pronounced and sustained intravascular volume expansion with 0.9% saline than with Hartmann's solution, urinary output was lower with 0.9% saline than with Hartmann's solution.(4545 Reid F, Lobo DN, Williams RN, Rowlands BJ, Allison SP. (Ab)normal saline and physiological Hartmann's solution: a randomized double-blind crossover study. Clin Sci (Lond). 2003;104(1):17-24.) The same group compared 0.9% saline with Plasma-Lyte (two liters within one hour) in twelve healthy volunteers on two separate occasions (up to 10 days apart).(4646 Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2012;256(1):18-24.) In this study, Plasma-Lyte and 0.9% saline produced similar intravascular volume expansion. Nevertheless, 0.9% saline yielded sustained hyperchloremia, reduced SID, increased extravascular volume (edema) and lowered diuresis compared with Plasma-Lyte.(4646 Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2012;256(1):18-24.) Additionally, renal artery flow velocity and renal cortical perfusion assessed with magnetic resonance imaging were significantly lower after 0.9% saline administration than after Plasma-Lyte. There was no difference in urinary NGAL.(4646 Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2012;256(1):18-24.)
STUDIES IN SEPTIC AND NON-SEPTIC CRITICALLY ILL PATIENTS
There is limited data available supporting the use of balanced solutions in septic shock patients.(77 Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, Mbuagbaw L, Szczeklik W, Alshamsi F, Altayyar S, Ip WC, Li G, Wang M, Wludarczyk A, Zhou Q, Guyatt GH, Cook DJ, Jaeschke R, Annane D; Fluids in Sepsis and Septic Shock Group. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014;161(5):347-55. Review.,88 Rochwerg B, Alhazzani W, Gibson A, Ribic CM, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, Mbuagbaw L, Szczeklik W, Alshamsi F, Altayyar S, Ip W, Li G, Wang M, Wludarczyk A, Zhou Q, Annane D, Cook DJ, Jaeschke R, Guyatt GH; FISSH Group (Fluids in Sepsis and Septic Shock) . Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis. Intensive Care Med. 2015;41(9):1561-71. Review.,1010 Orbegozo Cortés D, Rayo Bonor A, Vincent JL. Isotonic crystalloid solutions: a structured review of the literature. Br J Anaesth. 2014;112(6):968-81.) A meta-analysis including fourteen studies with 18,916 adult septic patients suggested that resuscitation with balanced crystalloids compared with unbalanced crystalloids (0.9% saline) may be associated with a lower mortality rate (odds ratio - OR, 0.78; 95% confidence interval - 95%CI, 0.58 to 1.05).(77 Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, Mbuagbaw L, Szczeklik W, Alshamsi F, Altayyar S, Ip WC, Li G, Wang M, Wludarczyk A, Zhou Q, Guyatt GH, Cook DJ, Jaeschke R, Annane D; Fluids in Sepsis and Septic Shock Group. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014;161(5):347-55. Review.) More recently, another network meta-analysis that included ten randomized clinical trials with 6,664 septic patients showed no significant difference in the need for renal replacement therapy (RRT) between balanced crystalloids and 0.9% saline (OR, 0.85; 95% CI, 0.56 to 1.30).(88 Rochwerg B, Alhazzani W, Gibson A, Ribic CM, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, Mbuagbaw L, Szczeklik W, Alshamsi F, Altayyar S, Ip W, Li G, Wang M, Wludarczyk A, Zhou Q, Annane D, Cook DJ, Jaeschke R, Guyatt GH; FISSH Group (Fluids in Sepsis and Septic Shock) . Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis. Intensive Care Med. 2015;41(9):1561-71. Review.)
Most studies comparing balanced and unbalanced crystalloids involved a mixed sample of clinical-surgical critically ill patients(2323 McFarlane C, Lee A. A comparison of Plasmalyte 148 and 0.9% saline for intra-operative fluid replacement. Anaesthesia. 1994;49(9):779-81.
24 Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal saline versus lactated Ringer's solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg. 2001;93(4):817-22.
25 Takil A, Eti Z, Irmak P, Yilmaz Gögüs F. Early postoperative respiratory acidosis after large intravascular volume infusion of lactated ringer's solution during major spine surgery. Anesth Analg. 2002;95(2):294-8, table of contents.
26 Young JB, Utter GH, Schermer CR, Galante JM, Phan HH, Yang Y, et al. Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial. Ann Surg. 2014;259(2):255-62.
27 Smith CA, Gosselin RC, Utter GH, Galante JM, Young JB, Scherer LA, et al. Does saline resuscitation affect mechanisms of coagulopathy in critically ill trauma patients? An exploratory analysis. Blood Coagul Fibrinolysis. 2015;26(3):250-4.
28 O'Malley CM, Frumento RJ, Hardy MA, Benvenisty AI, Brentjens TE, Mercer JS, et al. A randomized, double-blind comparison of lactated Ringer's solution and 0.9% NaCl during renal transplantation. Anesth Analg. 2005;100(5):1518-24, table of contents.
29 Khajavi MR, Etezadi F, Moharari RS, Imani F, Meysamie AP, Khashayar P, et al. Effects of normal saline vs. lactated ringer's during renal transplantation. Ren Fail. 2008;30(5):535-9.
30 Hadimioglu N, Saadawy I, Saglam T, Ertug Z, Dinckan A. The effect of different crystalloid solutions on acid-base balance and early kidney function after kidney transplantation. Anesth Analg. 2008;107(1):264-9.
31 Modi MP, Vora KS, Parikh GP, Shah VR. A comparative study of impact of infusion of Ringer's Lactate solution versus normal saline on acid-base balance and serum electrolytes during live related renal transplantation. Saudi J Kidney Dis Transpl. 2012;23(1):135-7.
32 Kim SY, Huh KH, Lee JR, Kim SH, Jeong SH, Choi YS. Comparison of the effects of normal saline versus Plasmalyte on acid-base balance during living donor kidney transplantation using the Stewart and base excess methods. Transplant Proc. 2013;45(6):2191-6.
33 Mahler SA, Conrad SA, Wang H, Arnold TC. Resuscitation with balanced electrolyte solution prevents hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis. Am J Emerg Med. 2011;29(6):670-4.
34 Van Zyl DG, Rheeder P, Delport E. Fluid management in diabetic-acidosis-Ringer's lactate versus normal saline: a randomized controlled trial. QJM. 2012;105(4):337-43.
35 Hasman H, Cinar O, Uzun A, Cevik E, Jay L, Comert B. A randomized clinical trial comparing the effect of rapidly infused crystalloids on acid-base status in dehydrated patients in the emergency department. Int J Med Sci. 2012;9(1):59-64.
36 Cieza JA, Hinostroza J, Huapaya JA, León CP. Sodium chloride 0.9% versus Lactated Ringer in the management of severely dehydrated patients with choleriform diarrhoea. J Infect Dev Ctries. 2013;7(7):528-32.-3737 Wu BU, Hwang JQ, Gardner TH, Repas K, Delee R, Yu S, et al. Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol. 2011;9(8):710-717.e1.,4848 Raghunathan K, Shaw A, Nathanson B, Stürmer T, Brookhart A, Stefan MS, et al. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis*. Crit Care Med. 2014;42(7):1585-91.
49 Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, McGuinness S, Mehrtens J, Myburgh J, Psirides A, Reddy S, Bellomo R; SPLIT Investigators; ANZICS CTG. Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. JAMA. 2015;314(16):1701-10.
50 Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308(15):1566-72.-5151 Shaw AD, Schermer CR, Lobo DN, Munson SH, Khangulov V, Hayashida DK, et al. Impact of intravenous fluid composition on outcomes in patients with systemic inflammatory response syndrome. Crit Care. 2015;19:334. Erratum in: Crit Care. 2016;20:17.) (Table 3). The safety and efficacy of volume expansion with a balanced crystalloid (Plasma-Lyte 148) compared with that of 0.9% saline were evaluated in a prospective, exploratory, cluster-randomized, blinded, double-crossover trial.(4949 Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, McGuinness S, Mehrtens J, Myburgh J, Psirides A, Reddy S, Bellomo R; SPLIT Investigators; ANZICS CTG. Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. JAMA. 2015;314(16):1701-10.) In this study, involving 2,278 critically ill patients, a median volume infusion of 2 liters of balanced crystalloid or 0.9% saline did not affect the risk of acute kidney injury (AKI) according to RIFLE (Risk, Injury, Failure, Loss, and End-Stage) classification (relative risk - RR, 1.04; 95%CI, 0.80 to 1.36; p = 0.77), the need for RRT (RR, 0.96; 95%CI, 0.62 to 1.50; p = 0.91), ICU (RR, 0.92; 95%CI, 0.68 to 1.24; p = 0.62) or in-hospital mortality (RR, 0.88; 95%CI, 0.67 to 1.17; p = 0.40).(4949 Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, McGuinness S, Mehrtens J, Myburgh J, Psirides A, Reddy S, Bellomo R; SPLIT Investigators; ANZICS CTG. Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. JAMA. 2015;314(16):1701-10.) Nevertheless, very few septic patients were included in this study, and acid-base and electrolyte parameters were not provided. This precluded determination regarding how much physiologic differentiation might have in fact occurred between the groups.(4949 Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, McGuinness S, Mehrtens J, Myburgh J, Psirides A, Reddy S, Bellomo R; SPLIT Investigators; ANZICS CTG. Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. JAMA. 2015;314(16):1701-10.) Furthermore, the effects on the primary outcome and other secondary binary outcomes were assessed with simple chi-squared tests, ignoring the lack of independence of each patient's observation caused by the cluster-randomized design of the study.(5252 Donner A. Some aspects of the design and analysis of cluster randomization trials. J R Stat Soc Ser C Appl Stat. 1998;47(1):95-113.) Consequently, the p-values were artificially high, and the 95% CI was over-narrowed.
A chloride-liberal strategy was compared with a chloride-restrictive strategy among critically ill adult patients in a before-after study.(5050 Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308(15):1566-72.) During a six-month control period (chloride-liberal period), 760 patients received intravenous fluids (0.9% saline, 4% succinylated gelatin solution or 4% albumin) according to the clinician's preference. After a 6-month interval, 773 patients received only chloride poor fluids (Hartmann's solution, Plasma-Lyte or 20% albumin).(5050 Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308(15):1566-72.) The authors demonstrated a significant decrease in acute kidney injury and failure (from 14.0% to 8.4%; p < 0.001) according to RIFLE classification and the need for RRT (from 10.0% to 6.3%; p = 0.005). No differences in in-hospital mortality or other clinical outcomes were observed.(5050 Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308(15):1566-72.) Contradictory findings were presented in a retrospective cohort study including 53,448 septic patients.(4848 Raghunathan K, Shaw A, Nathanson B, Stürmer T, Brookhart A, Stefan MS, et al. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis*. Crit Care Med. 2014;42(7):1585-91.) In this observational study, resuscitation with balanced crystalloids, but not with unbalanced crystalloids, was associated with decreased risk of in-hospital mortality (RR, 0.86; 95%CI, 0.78 to 0.94; p = 0.001). Nevertheless, no significant difference in the incidence of acute kidney injury, need for RRT, and hospital and ICU lengths of stay was reported.(4848 Raghunathan K, Shaw A, Nathanson B, Stürmer T, Brookhart A, Stefan MS, et al. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis*. Crit Care Med. 2014;42(7):1585-91.)
A propensity-matched cohort study with 3,116 hospitalized patients with a systemic inflammatory response syndrome (SIRS) showed that balance crystalloids (Plasma-Lyte or Normosol), compared with 0.9% saline, were associated with a lower rate of major complications (atrial fibrillation, congestive heart failure, acute respiratory failure, pneumonia, sepsis and coagulopathy), a lower frequency of electrolyte abnormalities and hyperchloremic acidosis, shorter length of hospital stay, less need for hospital re-admission, and lower in-hospital mortality.(5151 Shaw AD, Schermer CR, Lobo DN, Munson SH, Khangulov V, Hayashida DK, et al. Impact of intravenous fluid composition on outcomes in patients with systemic inflammatory response syndrome. Crit Care. 2015;19:334. Erratum in: Crit Care. 2016;20:17.) Nevertheless, the incidence of acute kidney injury did not differ between the groups studied.(5151 Shaw AD, Schermer CR, Lobo DN, Munson SH, Khangulov V, Hayashida DK, et al. Impact of intravenous fluid composition on outcomes in patients with systemic inflammatory response syndrome. Crit Care. 2015;19:334. Erratum in: Crit Care. 2016;20:17.)
Several small randomized trials compared balanced crystalloids with 0.9% saline(2323 McFarlane C, Lee A. A comparison of Plasmalyte 148 and 0.9% saline for intra-operative fluid replacement. Anaesthesia. 1994;49(9):779-81.
24 Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal saline versus lactated Ringer's solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg. 2001;93(4):817-22.
25 Takil A, Eti Z, Irmak P, Yilmaz Gögüs F. Early postoperative respiratory acidosis after large intravascular volume infusion of lactated ringer's solution during major spine surgery. Anesth Analg. 2002;95(2):294-8, table of contents.
26 Young JB, Utter GH, Schermer CR, Galante JM, Phan HH, Yang Y, et al. Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial. Ann Surg. 2014;259(2):255-62.
27 Smith CA, Gosselin RC, Utter GH, Galante JM, Young JB, Scherer LA, et al. Does saline resuscitation affect mechanisms of coagulopathy in critically ill trauma patients? An exploratory analysis. Blood Coagul Fibrinolysis. 2015;26(3):250-4.
28 O'Malley CM, Frumento RJ, Hardy MA, Benvenisty AI, Brentjens TE, Mercer JS, et al. A randomized, double-blind comparison of lactated Ringer's solution and 0.9% NaCl during renal transplantation. Anesth Analg. 2005;100(5):1518-24, table of contents.
29 Khajavi MR, Etezadi F, Moharari RS, Imani F, Meysamie AP, Khashayar P, et al. Effects of normal saline vs. lactated ringer's during renal transplantation. Ren Fail. 2008;30(5):535-9.
30 Hadimioglu N, Saadawy I, Saglam T, Ertug Z, Dinckan A. The effect of different crystalloid solutions on acid-base balance and early kidney function after kidney transplantation. Anesth Analg. 2008;107(1):264-9.
31 Modi MP, Vora KS, Parikh GP, Shah VR. A comparative study of impact of infusion of Ringer's Lactate solution versus normal saline on acid-base balance and serum electrolytes during live related renal transplantation. Saudi J Kidney Dis Transpl. 2012;23(1):135-7.
32 Kim SY, Huh KH, Lee JR, Kim SH, Jeong SH, Choi YS. Comparison of the effects of normal saline versus Plasmalyte on acid-base balance during living donor kidney transplantation using the Stewart and base excess methods. Transplant Proc. 2013;45(6):2191-6.
33 Mahler SA, Conrad SA, Wang H, Arnold TC. Resuscitation with balanced electrolyte solution prevents hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis. Am J Emerg Med. 2011;29(6):670-4.
34 Van Zyl DG, Rheeder P, Delport E. Fluid management in diabetic-acidosis-Ringer's lactate versus normal saline: a randomized controlled trial. QJM. 2012;105(4):337-43.
35 Hasman H, Cinar O, Uzun A, Cevik E, Jay L, Comert B. A randomized clinical trial comparing the effect of rapidly infused crystalloids on acid-base status in dehydrated patients in the emergency department. Int J Med Sci. 2012;9(1):59-64.
36 Cieza JA, Hinostroza J, Huapaya JA, León CP. Sodium chloride 0.9% versus Lactated Ringer in the management of severely dehydrated patients with choleriform diarrhoea. J Infect Dev Ctries. 2013;7(7):528-32.-3737 Wu BU, Hwang JQ, Gardner TH, Repas K, Delee R, Yu S, et al. Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol. 2011;9(8):710-717.e1.) (Table 3). In most trials, 0.9% saline induced hyperchloremic metabolic acidosis compared with either Ringer's lactate or Plasma-Lyte (Table 3). The effect of 0.9% saline versus Plasma-Lyte on coagulation (thromboelastography) was recently evaluated in eighteen trauma patients.(2727 Smith CA, Gosselin RC, Utter GH, Galante JM, Young JB, Scherer LA, et al. Does saline resuscitation affect mechanisms of coagulopathy in critically ill trauma patients? An exploratory analysis. Blood Coagul Fibrinolysis. 2015;26(3):250-4.) The time from 2 to 20mm amplitude (K) was shorter, and the α angle higher after intravascular expansion with Plasma-Lyte than with 0.9% saline.(2727 Smith CA, Gosselin RC, Utter GH, Galante JM, Young JB, Scherer LA, et al. Does saline resuscitation affect mechanisms of coagulopathy in critically ill trauma patients? An exploratory analysis. Blood Coagul Fibrinolysis. 2015;26(3):250-4.) Coagulation derangements secondary to crystalloid infusion may have clinical implications, as suggested by another study involving 66 patients undergoing aortic reconstructive surgery.(2424 Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal saline versus lactated Ringer's solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg. 2001;93(4):817-22.) In this study, patients who received 0.9% saline needed more platelets and blood product transfusion than did those who received Ringer's lactate.(2424 Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal saline versus lactated Ringer's solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg. 2001;93(4):817-22.) The effect of intravascular volume expansion with low-chloride versus high-chloride content crystalloids in critically ill or surgical patients was recently addressed in a meta-analysis.(5353 Krajewski ML, Raghunathan K, Paluszkiewicz SM, Schermer CR, Shaw AD. Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation. Br J Surg. 2015;102(1):24-36.) Twenty-one studies (15 randomized controlled trials) with 6,253 patients were included. Although high-chloride containing crystalloids did not affect mortality, they increased the risk of hyperchloremia and metabolic acidosis (risk ratio, 2.87; 95%CI, 1.95 to 4.21; p < 0.001) and the risk of acute kidney injury (risk ratio, 1.64; 95%CI, 1.27 to 2.13; p < 0.001).(5353 Krajewski ML, Raghunathan K, Paluszkiewicz SM, Schermer CR, Shaw AD. Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation. Br J Surg. 2015;102(1):24-36.) Finally, there was an increase in blood transfusion volume following resuscitation with 0.9% saline compared with low-chloride crystalloids.(5353 Krajewski ML, Raghunathan K, Paluszkiewicz SM, Schermer CR, Shaw AD. Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation. Br J Surg. 2015;102(1):24-36.)
In summary, the current literature suggests that resuscitation of septic and non-septic critically ill patients with unbalanced crystalloids, mainly 0.9% saline, is associated with a higher incidence of acid-base balance and electrolyte derangements. Most importantly, resuscitation with unbalanced crystalloids might be associated with increased bleeding risk, an increased need for transfusion, a higher incidence of acute kidney injury, an increased need for RRT and increased mortality.
FUTURE DIRECTIONS
Although it appears that all crystalloid solutions have similar hemodynamic effects,(1010 Orbegozo Cortés D, Rayo Bonor A, Vincent JL. Isotonic crystalloid solutions: a structured review of the literature. Br J Anaesth. 2014;112(6):968-81.) the impact of intravascular volume expansion with balanced solutions on regional and microcirculatory blood flow, tissue perfusion, mitochondrial function, systemic inflammation and coagulation need to be further evaluated in both experimental and clinical studies.(1010 Orbegozo Cortés D, Rayo Bonor A, Vincent JL. Isotonic crystalloid solutions: a structured review of the literature. Br J Anaesth. 2014;112(6):968-81.) Furthermore, this review, as with any non-systematic narrative review, may have limitations in terms of the comprehensiveness of the search strategy used to identify relevant papers and the lack of standardization of methods for data extraction, analysis and interpretation. Thus, systematic reviews with meta-analysis on the subject are warranted.
CONCLUSION
Adequate fluid replacement is crucial to maintain perfusion pressure and, ultimately, tissue perfusion in septic shock patients. Although the current sepsis guidelines recommend crystalloids as first-line fluids for septic shock resuscitation, in the light of the inconclusive nature of the available literature, no definitive recommendations on the most appropriate crystalloid solution can be made. Therefore, the safety and efficacy of balanced solutions, compared with 0.9% saline, for septic shock resuscitation should be further evaluated in a large, multicenter, pragmatic, randomized clinical trial.
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Responsible editor: Pedro Póvoa
ACKNOWLEDGEMENTS
We thank Helena Spalic for proofreading this manuscript.
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Publication Dates
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Publication in this collection
Oct-Dec 2016
History
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Received
22 June 2016 -
Accepted
08 Aug 2016